The characteristic neuropathological and molecular lesions that correlate with dementia in Alzheimer's Disease (AD) include the accumulation of hyper-phosphorylated and poly-ubiquinated microtubule-associated proteins, such as tau, resulting in the formation of neurofibrillary tangles, dystrophic neuritis, and neuropil threads. Neuronal cytoskeletal abnormalities are associated with cerebral atrophy with cell and fiber loss, and synaptic disconnection. Increased amyloid-beta (Aβ) deposition around and within the walls of meningeal and cortical vessels, the cortical neuropil, and neuronal perikarya is a feature of both AD and normal aging. Although genetic factors can predispose individuals to develop premature and excessive cerebral deposits of Aβ in AD-type dementia, most cases are sporadic and do not exhibit clear familial or genetic clustering. Recent exploration of biochemical, molecular, and cellular abnormalities that precede or accompany classic AD demonstrated that cell loss was associated with increased activation of pro-death genes and signaling pathways, impaired energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and cerebrovascular disease/cerebral hypoperfusion. However, the inability to interlink these phenomena under a single primary pathogenic mechanism resulted in the emergence and propagation of various heavily debated theories, each of which focused on how one particular component of AD could trigger a cascade that contributes to the development of all other known abnormalities.
Currently, the major pathological factors known to be involved in Alzheimer's Disease (AD) include beta amyloid accumulation, neurofibrillary tangles (NFTs) and synaptic dysfunction or loss. In addition, AD is associated with other pathological processes, including failing mitochondrial function and oxidative stress, increased inflammatory response, protein misfolding, altered growth factor signaling, aberrant reentry of neurons into the cell cycle, lysosomal activation, endocrine alteration, insulin resistance, cholesterol dyshomeostasis, and calcium dysregulation.
The complexity and number of changes associated with AD has impeded attempts to disentangle the processes important for pathogenesis and discover a treatment of AD. Therefore, there sill remains a need for identifying agents or molecules that can be used for diagnosis and/or treating AD.